Well over a decade ago, we demonstrated that the latent viral reservoir in the resting CD4+ T cell compartment persists in virtually all HIV-infected individuals receiving clinically effective ART. In addition, we demonstrated that HIV continually replicates at low levels in chronically infected individuals who are consistently aviremic during prolonged periods of receiving ART. Based on the above findings and similar observations from other groups, the persistent viral reservoir has become a major impediment to the eradication of HIV in infected individuals receiving ART. Consequently, a major current thrust of HIV therapeutic research is the development of strategies to eliminate HIV reservoirs and to achieve a cure for HIV infection. Considering that a complete eradication of HIV is not currently feasible in the majority of infected individuals, even under the best of circumstances involving early initiation of ART, new approaches aimed at containing viral replication are being considered. The aim is not necessarily to achieve complete eradication of the virus, but rather to passively transfer anti-HIV antibodies, to boost HIV-specific immune responses, and/or other immune related agents in order to keep plasma viremia in check upon discontinuation of ART. Over the past year, we conducted a clinical trial to investigate the feasibility of achieving sustained virologic remission in HIV-infected individuals through multiple infusions of VRC01 following the cessation of ART. Recent advances in antibody cloning technologies have led to the discovery of a number of highly potent bNAbs from B cells of HIV-infected individuals. It has been shown that certain bNAbs can prevent acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral rebound following treatment interruption in animal models and a small number of HIV-infected viremic individuals. However, it has been unclear what in vivo effects these antibodies might have on plasma viral rebound in HIV-infected individuals following discontinuation of ART. Given that virtually all infected individuals who initiated ART during the chronic phase of infection experience plasma viral rebound upon cessation of therapy, it is of great interest to investigate whether a potent bNAb, such as VRC01, can prevent plasma viral rebound in infected individuals whose antiretroviral drugs have been discontinued. We enrolled 10 subjects with prolonged suppression of plasma viremia on ART (median 8.3 years) in our passive antibody transfer trial. The study subjects received between 2 to 6 infusions (median 3.5) of VRC01, with no adverse events occurring during the infusion or immediate post-infusion period. Levels of plasma VRC01 were above 100g/mL at almost all time-points throughout the study, suggesting that sufficient levels of antibody were maintained in vivo. Nonetheless, all 10 subjects experienced plasma viral rebound (>40 copies/ml) between 11-86 days (median 39) following cessation of ART. Baseline HIV isolates recovered from study subjects revealed evidence of pre-existing VRC01-resistent virus. Additionally, emergence of VRC01-resisistant HIV was detected during plasma viral rebound in the majority of study subjects. Given the inability of a single bNAb to sustain virologic remission in the absence of ART, future therapeutic strategies involving passive transfer of bNAbs will likely require a combination(s) of antibodies and/or resistance prescreening similar to approaches used with combination ART. In addition to the aforementioned clinical study, we have an on-going clinical trial designed to examine the effect of therapeutic vaccination on plasma viral rebound in HIV-infected individuals following discontinuation of ART. This is a randomized, 2-arm (1:1, 15 patients per arm), double-blind, placebo-controlled trial evaluating the safety and efficacy of an HIV multi-antigen plasmid DNA vaccine prime, in combination with an interleukin-12 plasmid DNA adjuvant delivered in vivo by electroporation, and a rVSV vaccine boost in subjects receiving ART who initiated therapy during the acute/early phase of HIV infection. Study subjects were randomized to receive placebo or the multi-antigen HIV DNA vaccine at week 0, 4, 12, and 36 and the rVSV HIV gag booster vaccine at week 24 and 48. After the week 56 visit, study subjects underwent treatment interruption to determine if the vaccination strategy resulted in a reduction of viral replication, as evidenced by blunted or absent rebound HIV plasma viremia. This clinical trial is now fully enrolled. All participants have already completed the vaccination phase of the study and have discontinued ART. Although the study remains blinded at the present time, we have begun extensive immunologic and virologic analyses on longitudinal specimens obtained from these study subjects. These analyses include a variety of laboratory assays that are designed to measure 1) plasma viremia following discontinuation of ART, 2) immunologic responses of CD4+ and CD8+ T cell populations to the study vaccines; 3) the impact of vaccination on the persistent HIV reservoir in the CD4+ T cell compartment and on plasma viral rebound upon discontinuation of ART; and 4) identification of predictors and correlates of virologic control in the absence of ART. We expect that this clinical trial will be concluded by April 2017.